Sealing the Leaky Gut Represents a Beneficial Mechanism of Zinc Intervention for Alcoholic Liver Disease

Abstract Alcoholic liver disease (ALD) is one of the major causes of liver-related mortality worldwide. However, FDA-approved therapies are currently not available. The major obstacle is the limited understanding of the pathogenesis of ALD. Zinc deficiency is one of the most consistent nutritional and biochemical observations in ALD, which plays an etiologic role in disease progression. Meanwhile, evidence suggests that endotoxemia because of gut leakiness critically mediates the development of ALD. Zinc deficiency disrupts the epithelial barrier function by disassembling tight junction proteins in addition to its direct detrimental effects on the liver, whereas dietary zinc supplementation protects against ALD. In this chapter, we review and discuss (1) the mechanisms of alcohol-induced gut barrier dysfunction to better understand the contribution of the gut-liver axis to the pathogenesis of ALD, (2) biological function and metabolism of zinc, (3) occurrence, mechanisms, and consequences of acquired zinc deficiency in ALD, which is mediated, in part, by impaired intake and absorption, increased excretion, and oxidative stress–induced mobilization, and (4) applications and mechanisms of zinc intervention for ALD. Importantly, the protection against ALD by dietary zinc supplementation involves multiple extrahepatic factors, including upregulated intestinal tight junction expressions, elevated aldehyde dehydrogenase activity, induced hepatocyte nuclear factor 4α function, and possibly modulated gut microbiota homeostasis. In summary, both human and animal studies suggest that zinc intervention might be an attractive therapy for ALD and that the protection by zinc against ALD includes both hepatic and extrahepatic actions.